Expressions of Angptl 3 and Angptl 4 in invasive breast cancer and clinical significance

doi:10.3877/cma.j.issn.1674-0807.2016.02.003

Abstract

Abstract:

Objective

To detect the expressions of angiopoietin-like proteins (Angptl) 3 and Angptl 4 in invasive breast cancer and the clinical significance, and explore the potentials as biomarkers for the treatment and prognosis of breast cancer.

Methods

The tumor samples surgically resected from 70 cases of invasive breast cancer and 30 cases of breast fibroadenoma in Subei People's Hospital from 2007 to 2009 were collected to determine the expressions of Angptl 3 and Angptl 4 with immunohistochemical SP method. χ² test was used to analyze the expression difference of these two proteins between invasive breast cancer and breast fibroadenoma.χ² test and Fisher's exact probability method were used to analyze the relationship between the protein expression and clinicopathological characteristics of invasive breast cancer. Spearman correlation analysis was used to detect the correlation between Angptl 3 and Angptl 4 in invasive breast cancer. Kaplan-Meier method and Cox model were used for survival analysis.

Results

The positive rate of Angptl 3 was 75.7%(53/70)in invasive breast cancer and 46.7% (14/30)in breast fibroadenoma (χ² = 8.014, P=0.005); the positive rate of Angptl 4 was 68.6%(48/70)in invasive breast cancer and 36.7%(11/30)in breast fibroadenoma (χ²=8.837, P=0.003), both indicating a significant difference. In 70 cases of invasive breast cancer, Angptl 3 expression showed a significant difference in patients with different tumor size, axillary lymph node metastasis, TNM stage and ER status(χ²=6.000, 5.598, 9.714, 8.753,P＜0.050); Angptl 4 expression showed a significant difference in patients with different tumor size, axillary lymph node metastasis and TNM stage (χ²=8.762,6.526,5.701, P＜0.050); Angptl 3 was positively correlated with Angptl 4(P=0.005, r=0.334). Kaplan-Meier analysis showed that the survival in patient with Angptl 3 /Angptl 4 positive was superior to that in patient with Angptl 3/Angptl 4 negative (χ²=9.376,7.628;P=0.002,0.006). Cox multivariate survival analysis showed that age, histological grade, tumor size, ER and PR status were independent risk factors in prognosis of invasive breast patients (OR=6.379,0.033,66.678,0.014,0.094;all P＜0.050;95%CI:1.380-29.482,0.002-0.598,5.433-818.294,0.001-0.183,0.012-0.724), while Angptl 3 and Angptl 4 expressions were not (OR=1.262,1.841;P=0.937,0.695; 95%CI:0.000-2.281,0.087-39.051).

Conclusions

Angptl 3 and Angptl 4 are highly expressed in invasive breast cancer, with a positive correlation. The patients with Angptl 3 and Angptl 4 positive have a short survival,however the two are not the independent risk factors in the prognosis of invasive breast caner patients.

Key words: Breast neoplasms, Angiopoietins, Immunohistochemistry, Prognosis

Fengfeng Mao, Jiaxin Zhang. Expressions of Angptl 3 and Angptl 4 in invasive breast cancer and clinical significance[J]. Chinese Journal of Breast Disease(Electronic Edition), 2016, 10(02): 76-81.

/ / Recommend

Add to citation manager EndNote|Ris|BibTeX

URL: https://zhrxbzz.cma-cmc.com.cn/EN/10.3877/cma.j.issn.1674-0807.2016.02.003

https://zhrxbzz.cma-cmc.com.cn/EN/Y2016/V10/I02/76

Figures/Tables 6

References 21

[1]	Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015[J]. CA Cancer J Clin,2015,65(1):5-29.
[2]	Hato T, Tabata M, Oike Y. The role of angiopoietin-like proteins in angiogenesis and metabolism[J]. Trends Cardiovasc Med, 2008, 18(1):6-14.
[3]	Yu J, Kane S, Wu J, et al. Mutation-specific antibodies for the detection of EGFR mutations in non-small-cell lung cancer. Clin Cancer Res,2009,15(9):3023-3028.
[4]	Kim I, Kwak HJ, Ahn JE, et al. Molecular cloning and characterization of a novel angiopoietin family protein, angiopoietin-3[J]. FEBS Lett,1999,443(3):353-356.
[5]	Köster A, Chao YB, Mosior M, et al. Transgenic angiopoietin -like(angptl) 4 overexpression and targeted disruption of angptl 4 and angptl 3:regulation of triglyceride metabolism[J]. Endocrinology, 2005, 146(11):4943-4950.
[6]	Kaplan R, Zhang T, Hernandez M, et al. Regulation of the angiopoietin-like protein 3 gene by LXR[J]. J Lipid Res, 2003, 44(1):136-143.
[7]	Shimizugawa T, Ono M, Shimamura M, et al. ANGPTL3 decreases very low density lipoprotein triglyceride clearance by inhibition of lipoprotein lipase[J]. J Biol Chem,2002,277(37):33 742-33 748.
[8]	Shimamura M,Matsuda M,Yasumo H,et al. Angiopoietin-like protein 3 regulates plasma HDL cholesterol through suppression of endothelial lipase[J]. Arterioscler Thromb Vasc Biol,2007,27(2):366-372.
[9]	Ono M, Shimizugawa T, Shimamura M, et al. Protein region important for regulation of lipid metabolism in angiopoietin-like 3 (ANGPTL3):ANGPTL3 is cleaved and activated in vivo[J]. J Biol Chem, 2003,278(43):41 804-41 809.
[10]	宋其同, 单云峰, 周蒙滔, 等. 血管生成素样蛋白3 的表达及其与肝细胞癌侵袭和生长的关系研究[J].中华肝胆外科杂志,2006,12(7):450-452.
[11]	Hayashi SI,Eguchi H, Tanimoto K,et al. The expression and function of estrogen receptor alpha and beta in human breast cancer and its clinical application [J]. Endocr Relat Cancer,2003,10(2):193-202.
[12]	Reis-Filho JS, Tutt AN. Triple negative tumours: a critical review[J]. Histopathology,2008,52(1):108-118.
[13]	Gentil C, Le Jan S, Philippe J, et al. Is oxygen a key factor in the lipodystrophy phenotype? [J]. Lipids Health Dis,2006,18 (5):27.
[14]	Kersten S, Mandard S, Tan NS, et al. Characterization of the fastinginduced adipose factor FIAF, a novel peroxisome proliferator-activated receptor target gene [J]. J Biol Chem,2000,275(37):28 488-28 493.
[15]	Yoshida K, Shimizugawa T, Ono M, et al. Angiopoietin-like protein 4 is a potent hyperlipidemia-inducing factor in mice and inhibitor of lipoprotein lipase[J]. J Lipid Res,2002,43(11):1770-1772.
[16]	Kim SH, Park YY, Kim SW, et al. ANGPTL4 induction by prostaglandin E2 under hypoxic conditions promotes colorectal cancer progression [J]. Cancer Res,2011,71(22):7010-7020.
[17]	Le Jan S, Amy C, Cazes A, et al. Angiopoietin-like 4 is a proangiogenic factor produced during ischemia and in conventional renal cell carcinoma [J]. Am J Pathol,2003,162(5):1521-1528.
[18]	Huang RL, Teo Z, Chong HC, et al. ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters[J]. Blood,2011,118(14):3990-4002.
[19]	Li H, Ge C, Zhao F, et al. Hypoxia-inducible factor 1 alpha-activated angiopoietin-like protein 4 contributes to tumor metastasis via vascular cell adhesion molecule-1/integrin β1 signaling in human hepatocellular carcinoma[J]. Hepatology,2011,54(3):910-919.
[20]	Hattori N, Okochi-Takada E, Kikuyama M, et al. Methylation silencing of angiopoietin-like 4 in rat and human mammary carcinomas[J]. Cancer Sci,2011,102(7):1337-1343.
[21]	Yoon JC, Chickering TW, Rosen ED, et al. Peroxisome proliferatoractivated receptor gamma target gene encoding a novel angiopoietinrelated protein associated with adipose differentiation [J]. Mol Cell Biol,2000,20(14):5343-5349.

变量	赋值
年龄	＜50岁=0;≥50岁=1
组织学分级	1级=0;2、3级=1
淋巴结转移	无转移=0;有转移=1
肿瘤直径	≤2 cm=0;＞2 cm=1
ER	阳性=0;阴性=1
PR	阳性=0;阴性=1
HER-2	阳性=0;阴性=1
TNM分期	Ⅰ、Ⅱ期=0;Ⅲ、Ⅳ期=1
Angptl 3	阳性=0;阴性=1
Angptl 4	阳性=0;阴性=1
生存时间	连续变量
生存结局	死亡=0;删失=1

变量	赋值
年龄	＜50岁=0;≥50岁=1
组织学分级	1级=0;2、3级=1
淋巴结转移	无转移=0;有转移=1
肿瘤直径	≤2 cm=0;＞2 cm=1
ER	阳性=0;阴性=1
PR	阳性=0;阴性=1
HER-2	阳性=0;阴性=1
TNM分期	Ⅰ、Ⅱ期=0;Ⅲ、Ⅳ期=1
Angptl 3	阳性=0;阴性=1
Angptl 4	阳性=0;阴性=1
生存时间	连续变量
生存结局	死亡=0;删失=1

变量	B值	标准误	Wald值	P值	OR值	95%CI
年龄	1.853	0.781	5.630	0.018	6.379	1.380～29.482
组织学分级	-3.400	1.472	5.331	0.021	0.033	0.002～0.598
肿瘤直径	4.200	1.279	10.778	0.001	66.678	5.433～818.294
ER	-4.255	1.304	10.657	0.001	0.014	0.001～0.183
PR	-2.364	1.042	5.150	0.023	0.094	0.012～0.724

变量	B值	标准误	Wald值	P值	OR值	95%CI
年龄	1.853	0.781	5.630	0.018	6.379	1.380～29.482
组织学分级	-3.400	1.472	5.331	0.021	0.033	0.002～0.598
肿瘤直径	4.200	1.279	10.778	0.001	66.678	5.433～818.294
ER	-4.255	1.304	10.657	0.001	0.014	0.001～0.183
PR	-2.364	1.042	5.150	0.023	0.094	0.012～0.724

Please choose a citation manager

Content to export